Abstract
Background
Cancer-related incident bone pain is a form of breakthrough pain caused by movement and is most commonly associated with bone metastases. It is often distinguished from other common forms of bone pain such as arthritis or the pain associated from the administration of filgrastim-like products that are usually constant in nature and worse at night. Management of incident bone pain often requires a multimodal approach as the onset of oral immediate release (IR) opioids may be too slow to address a rapid-onset pain elicited by activity. 1 Cancer-related incident bone pain is correlated with a decreased patient-reported quality of life, a reduced functional capacity, as well as increased psychological distress. 2 Although there is not a clear association with the size, location, or number of bone metastasis,2,3 ∼70% of patients with bone metastases will develop pain. 4
Pathophysiology
Bone metastases occur in up to 70% of those with prostate and breast cancer and up to 30% of those with cancers of the lung, bladder, and thyroid. 5 Osteolytic lesions (associated with multiple myeloma, lung, thyroid, kidney, and breast cancer), osteoblastic lesions (usually associated with prostate cancer), and mixed lesions (associated with lymphoma, breast, and lung cancer) all can cause pain through increased bone destruction, bone remodeling, and the loss of bone integrity. 2 This process causes pain through the production of inflammatory by-products such as prostacyclins and cytokines that activate sensory nerves to transmit painful stimuli to the central nervous system.2,6 The pain is usually intense, easy to localize, and sudden in onset. 1 Maximal pain usually occurs in 3 minutes and lasts 30 minutes after movement.1,7,8
Diagnostics
Depending on the oncological situation, plain radiography, skeletal scintigraphy (aka bone scans for osteolytic lesions), computed tomography, magnetic resonance imaging, and positron emission tomography can identify if bone metastases match up with the site of pain. 9 Oncologists can help in determining the appropriate radiological study.
Analgesic Options
For ambulatory patients, many experts recommend a multimodal analgesic approach in which all the following analgesic options, including interventional ones, are considered simultaneously in the hopes of maximizing analgesia and functional capacity. As patients become moribund and less ambulatory from the dying process, cancer-related bone pain often diminishes.
Opioids
There are several challenges in determining the best opioid dose, regimen, and timing for incident bone pain. First, many oral IR opioids have an onset of action around 20–40 minutes, which is often too delayed to manage bone pain brought on by activity. Furthermore, if scheduled opioids are dosed to manage pain at rest, they often are underdosed for ambulation. Conversely, if scheduled opioids are based on ambulation pain requirements, patients may feel oversedated at rest.
The limited data available suggest that regularly scheduled long-acting opioids or basal opioid infusions provide better symptom relief, compared with only as needed fast acting opioids, even at initial doses and even for patients with little to no pain at rest. 1
For activities that reliably incite pain (e.g., a physical therapy session), some experts suggest a trial dose of a prophylactic IR opioid given 20–30 minutes before the activity.
A few industry-supported studies suggest that transmucosal fentanyl may have a quicker onset of analgesia (5–15 minutes) and superior analgesia compared with IR morphine for incident-bone pain (see Fast Facts #103 and #331).7,8 Potential benefits of transmucosal fentanyl must be weighed against their considerable cost and regulatory and accessibility issues.7,8
External beam radiotherapy
Single fraction radiotherapy can offer analgesia in 24–48 hours for many patients with incident bone pain with similar efficacy as multifraction radiotherapy (see Fast Fact #335). 10 Despite its effectiveness, 20%–30% of patients treated with external beam radiotherapy still experience refractory bone pain and may require additional analgesic modalities. 11
Anti-inflammatories
Despite their widespread use, data supporting the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids for bone metastases pain remain limited.12,13 Surveys of palliative medicine providers show that dexamethasone 4–8 mg by mouth daily is the most commonly used corticosteroid for metastatic bone pain. 13 No NSAID is proven to be superior over any other, but some experts suggest a three-day course of parenteral ketorolac 30 mg q8 in the inpatient setting for patients <65 years without a history of thrombocytopenia, renal failure, or gastrointestinal toxicities. 14 Co-prescription of a H2 blocker (e.g., famotidine) or a proton pump inhibitor is often advised with NSAIDs. 14
Bisphosphonates
Bisphosphonates are associated with bone stabilization and analgesia through bone resorption and increasing the pH of the tumor environment (see Fast Fact #113). 9 Analgesia typically begins within a week and lasts 12 weeks. Zoledronic acid and pamidronate have the best supporting evidence in this medication class and are usually prescribed by the treating oncologist.11,15
Radiopharmaceuticals
See Fast Fact #116. In patients with widespread painful bone metastases, the use of an injected intravenous radioactive isotopes such as 89Sr (strontium), 153Sm (samarium), or 223R (radium, which is commonly utilized for prostate cancer) can target radiation to all metastatic skeletal sites and provide significant analgesia in up to 75% of selected patients. 5 Onset of pain relief is usually one to three weeks and may last six months. Myelosuppression and renal insufficiency are relative contraindications.
Cryoablation and radiofrequency ablation
These minimally invasive procedures are usually performed by interventional radiologists to direct either localized cold (cryoablation) or heat (radiofrequency ablation) to destroy metastatic lesions. They have been associated with improved analgesia of incident-bone pain.16,17 General anesthesia, conscious sedation, or short postprocedure hospitalization may be required.
Adjuvant therapies
Animal model studies suggest that carbenoxolone may become a promising analgesic for cancer-induced bone pain. 18 Although commonly prescribed, there is insufficient evidence to strongly recommend antidepressants, scheduled acetaminophen, ketamine, topical lidocaine, acupuncture, or massage for the treatment of incident bone pain.12,19,20